Escherichia coli (E. coli) is one of the major causes of nosocomial pneumonia. Moreover, E. coli pneumonia may also be community-acquired in patients who have underlying disease such as diabetes mellitus, alcoholism, and chronic obstructive pulmonary disease. Although inappropriate inflammatory host responses play a central role in the pathogenesis of pneumonia, the precise molecular mechanisms underlying the development of this disorder remain poorly understood. Altered calcium homeostasis is considered to play an important role in inflammation. Although the predominant mechanisms to raise intracellular calcium used by most immune cells is store-operated Ca2+ entry (SOCE) whereby the depletion of endoplasmic reticulum (ER) Ca2+ stores triggers the influx of extracellular Ca2+, the direct molecular basis of SOCE activation was unknown until the recent identification of stromal interaction molecule 1 (STIM1) as the critical ER Ca2+ sensor. However, the significance of STIM1 and SOCE in in vivo inflammatory responses, immunity to infection, and other immune-related diseases remains largely unknown. Using the Cre recombinase-loxP system, we recently generated mice with specific deletion of the gene encoding STIM1 in myeloid cells (STIM1-/-). Our preliminary data indicate that STIM1 deficiency significantly reduced E. coli-induced IL-6, KC, IL-1b, and MCP-1 levels in bronchoalveolar lavage (BAL) fluids and neutrophil accumulation in the lung compared to WT mice (STIM1+/+). Furthermore, E. coli-stimulated STIM1-/- mice showed significantly reduced lung transcription factors CCAAT/enhancer-binding proteins (C/EBPs) activation (mainly C/EBP?). We further show that STIM1 interacts with Orai1 and TRPC1, important Ca2+ channels for SOCE in immune cells. Based on these studies, we hypothesize that STIM1 plays an important regulatory role in lung inflammatory responses to E. coli and host defense against E. coli pneumonia by interacting with Orai1, TRPC1, and other signaling molecules. Therefore, this exploratory study is designed to define the roles of STIM1 in E. coli- induced pulmonary alveolitis and the underlying molecular mechanisms. Two specific aims are proposed to test our hypothesis. In the first aim, we will determine the role of STIM1 in the lungs against E. coli infection. In the second aim, we will elucidate the molecular mechanisms of STIM1 function in the E. coli pneumonia. The results of our studies are expected to provide important novel information on the regulatory roles of STIM1 in the lung inflammatory responses to bacteria. This knowledge will represent a new paradigm for approaching the development of novel therapeutic targets for treatment of pneumonia.